This application claims the benefit of U.S. provisional application Ser. No. 60/297,629 filed on 12 Jun. 2001, under 35 USC 119(e)(i); U.S. provisional application Ser. No. 60/297,630 filed on 12 Jun. 2001, under 35 USC 119(e)(i); U.S. provisional application Ser. No. 60/297,631 filed on 12 Jun. 2001, under 35 USC 119(e)(i); U.S. provisional application Ser. No. 60/297,632 filed on 12 Jun. 2001, under 35 USC 119(e)(i); U.S. provisional application Ser. No. 60/297,633 filed on 12 Jun. 2001, under 35 USC 119(e)(i); U.S. provisional application Ser. No. 60/328,548 filed on Oct. 11, 2001, under 35 USC 119(e)(i); and U.S. provisional application Ser. No. 60/373,496 filed on 18 Apr. 2002, under 35 USC 119(e)(i), which are incorporated herein by reference in their entirety.
Nicotinic acetylcholine receptors (nAChRs) play a large role in central nervous system (CNS) activity. Particularly, they are known to be involved in cognition, learning, mood, emotion, and neuroprotection. There are several types of nicotinic acetylcholine receptors, and each one appears to have a different role in regulating CNS function. Nicotine affects all such receptors, and has a variety of activities. Unfortunately, not all of the activities are desirable. In fact, one of the least desirable properties of nicotine is its addictive nature and the low ratio between efficacy and safety. The present invention relates to molecules that have a greater effect upon the xcex17 nAChRs as compared to other closely related members of this large ligand-gated receptor family. Thus, the invention provides compounds that are active drug molecules with fewer side effects.
Cell surface receptors are, in general, excellent and validated drug targets. nAChRs comprise a large family of ligand-gated ion channels that control neuronal activity and brain function. These receptors have a pentameric structure. In mammals, this gene family is composed of nine alpha and four beta subunits that co-assemble to form multiple subtypes of receptors that have a distinctive pharmacology. Acetylcholine is the endogenous regulator of all of the subtypes, while nicotine non-selectively activates all nAChRs.
The xcex17 nAChR is one receptor system that has proved to be a difficult target for testing. Native xcex17 nAChR is not routinely able to be stably expressed in most mammalian cell lines (Cooper and Millar, Nature, 366(6454), p. 360-4, 1997). Another feature that makes functional assays of xcex17 nAChR challenging is that the receptor is rapidly (100 milliseconds) inactivated. This rapid inactivation greatly limits the functional assays that can be used to measure channel activity.
Recently, Eisele et al. has indicated that a chimeric receptor formed between the N-terminal ligand binding domain of the xcex17 nAChR (Eisele et al., Nature, 366(6454), p 479-83, 1993), and the pore forming C-terminal domain of the 5-HT3 receptor expressed well in Xenopus oocytes while retaining nicotinic agonist sensitivity. Eisele et al. used the N-terminus of the avian (chick) form of the xcex17 nAChR receptor and the C-terminus of the mouse form of the 5-HT3 gene. However, under physiological conditions the xcex17 nAChR is a calcium channel while the 5-HT3R is a sodium and potassium channel. Indeed, Eisele et al. teaches that the chicken xcex17 nAChR/mouse 5-HT3R behaves quite differently than the native xcex17 nAChR with the pore element not conducting calcium but actually being blocked by calcium ions. WO 00/73431 A2 reports on assay conditions under which the 5-HT3R can be made to conduct calcium. This assay may be used to screen for agonist activity at this receptor.
WO 00/73431 A2 discloses two binding assays to directly measure the affinity and selectivity of compounds at the xcex17 nAChR and the 5-HT3R. The combined use of these functional and binding assays may be used to identify compounds that are selective agonists of the xcex17 nAChR.
The present invention discloses compounds of the Formula I: 
wherein W0 is a bicyclic moiety and is 
X is O, or S;
R1 is H, alkyl, cycloalkyl, halogenated alkyl, substituted phenyl, or substituted naphthyl;
R2 is H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, or aryl;
R3 is H, F, alkyl, halogenated alkyl, substituted alkyl, lactam heterocycloalkyl, phenoxy, substituted phenoxy, R7, R9, xe2x80x94N(R4)-aryl, xe2x80x94N(R4)-substituted phenyl, xe2x80x94N(R4)-substituted naphthyl, xe2x80x94O-substituted phenyl, xe2x80x94O-substituted naphthyl, xe2x80x94S-substituted phenyl, xe2x80x94S-substituted naphthyl, or alkyl substituted on the xcfx89 carbon with R15 where said xcfx89 carbon is determined by counting the longest carbon chain of the alkyl moiety with the C-1 carbon being the carbon attached to the bicyclic moiety W0 and the xcfx89 carbon being the carbon furthest, e.g., separated by the greatest number of carbon atoms in the chain, from said C-1 carbon;
W is C(H) where
Vxe2x80x94Zxe2x80x94Y is selected from Oxe2x80x94C(R3)xe2x95x90N, Oxe2x80x94C(R5)(R3)xe2x80x94N(R4), Oxe2x80x94C(R5)(R3)xe2x80x94S, Oxe2x80x94Nxe2x95x90C(R5), Oxe2x80x94C(R3)(R8)xe2x80x94O, Oxe2x80x94C(R3)(R5)xe2x80x94O, Sxe2x80x94C(R3)xe2x95x90N, Sxe2x80x94C(R5)(R3)xe2x80x94N(R4), Sxe2x80x94Nxe2x95x90C(R5), Nxe2x95x90C(R3)xe2x80x94O, Nxe2x95x90C(R3)xe2x80x94S, Nxe2x95x90C(R3)xe2x80x94N(R4), N(R4)xe2x80x94Nxe2x95x90C(R5), N(R4)xe2x80x94C(R5)(R3)xe2x80x94O, N(R4)xe2x80x94C(R5)(R3)xe2x80x94S, N(R4)xe2x80x94C(R5)(R3)xe2x80x94N(R4), C(R4)2xe2x80x94Oxe2x80x94N(R4), C(R5)2xe2x80x94N(R4)xe2x80x94O, C(R5)2xe2x80x94N(R4)xe2x80x94S, C(R5)xe2x95x90Nxe2x80x94O, C(R5)xe2x95x90Nxe2x80x94S, C(R5)xe2x95x90Nxe2x80x94N(R4), C(R5)2xe2x80x94Oxe2x80x94C(R5)2, C(R5)2xe2x80x94Sxe2x80x94C(R5)2, C(R5)2xe2x80x94N(R4)xe2x80x94C(R5)2, C(R5)(R17)xe2x80x94C(R3)(R17)xe2x80x94C(R5)(R17), or C(R5)2xe2x80x94C(R3)(R5)xe2x80x94C(R5)xe2x80x94C(R5)2;
Q is N(R19), O, or S;
W is N where
Vxe2x80x94Zxe2x80x94Y is selected from Oxe2x80x94C(R3)xe2x95x90N, Oxe2x80x94C(R5)(R3)xe2x80x94N(R4), Oxe2x80x94C(R5)(R3)xe2x80x94S, Oxe2x80x94Nxe2x95x90C(R5) Oxe2x80x94C(R3)(R5)xe2x80x94O, Sxe2x80x94C(R3)xe2x95x90N, Sxe2x80x94C(R5)(R3)xe2x80x94N(R4), Sxe2x80x94Nxe2x95x90C(R5), Nxe2x95x90C(R3)xe2x80x94O, Nxe2x95x90C(R3)xe2x80x94S, Nxe2x95x90C(R3)xe2x80x94N(R4), N(R4)xe2x80x94Nxe2x95x90C(R5), N(R4)xe2x80x94C(R5)(R3)xe2x80x94O, N(R4)xe2x80x94C(R5)(R3)xe2x80x94S, N(R4)xe2x80x94C(R5)(R3)xe2x80x94N(R4), C(R5)2xe2x80x94Oxe2x80x94N(R4), C(R5)2xe2x80x94N(R4)xe2x80x94O C(R5)2xe2x80x94N(R4)xe2x80x94S, C(R5)xe2x95x90Nxe2x80x94O, C(R5)xe2x95x90Nxe2x80x94S, C(R5)xe2x95x90Nxe2x80x94N(R4), C(R5)xe2x95x90C(R3)xe2x80x94C(R5)2, or C(R5)2xe2x80x94C(R3)(R5)xe2x80x94C(R5)2;
W1, W2, W3, W4 are each independently N or C(R21), provided that no more than two of W1, W2, W3, W4 are N, and further provided when more than two of W1, W2, W3, W4 are C(R21) that no more than two R21 are other than H;
J is N(R23), S, or O;
R4 is H, or alkyl;
R5 is H, F, Br, Cl, I, alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, heterocycloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OR1, xe2x80x94C(O)N(R16)2, xe2x80x94NHR1, xe2x80x94NR1COR16, xe2x80x94N(R10)2, xe2x80x94SR1, xe2x80x94C(O)R16, xe2x80x94CO2R1, aryl, R7, or R9;
R6 is H, F, Cl, Br, I, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OR16, xe2x80x94SR16, or xe2x80x94N(R16)2;
R7 is 5-membered heteroaromatic mono-cyclic moieties containing within the ring 1-3 heteroatoms independently selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x95x90Nxe2x80x94, xe2x80x94N(R19)xe2x80x94, and xe2x80x94Sxe2x80x94, and having 0-1 substituent selected from R20 and further having 0-3 substituents independently selected from F, Cl, Br, or I, or R7 is 9-membered fused-ring moieties having a 6-membered ring fused to a 5-membered ring and having the formula 
wherein E is O, S, or NR19, 
wherein E and G are independently selected from CR18, O, S, N, or NR19, and A is CR18 or N, or 
wherein E and G are independently selected from CR18, O, S, N, or NR19, and A is CR18 or N, each 9-membered fused-ring moiety having 0-1 substituent selected from R20 and further having 0-3 substituent(s) independently selected from F, Cl, Br, or I, and having a bond directly or indirectly attached to the core molecule where valency allows in either the 6-membered or the 5-membered ring of the fused-ring moiety;
Each R8 is independently F, Br, Cl, I, alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OR1, xe2x80x94C(O)NH2, xe2x80x94NHR1, xe2x80x94SR1, xe2x80x94CO2R1, aryl phenoxy, substituted phenoxy, heteroaryl, xe2x80x94N(R4)-aryl, or xe2x80x94O-substituted aryl.
R9 is 6-membered heteroaromatic mono-cyclic moieties containing within the ring 1-3 heteroatoms selected from xe2x95x90Nxe2x80x94 and having 0-1 substituent selected from R20 and 0-3 substituent(s) independently selected from F, Cl, Br, or I, or R9 is 10-membered heteroaromatic bi-cyclic moieties containing within one or both rings 1-3 heteroatoms selected from xe2x95x90Nxe2x80x94, including, but not limited to, quinolinyl or isoquinolinyl, each 10-membered fused-ring moiety having 0-1 substituent selected from R20 and 0-3 substituent(s) independently selected from F, Cl, Br, or I and having a bond directly or indirectly attached to the core molecule where valency allows;
Each R10 is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 substituent selected from R13, cycloalkyl substituted with 1 substituent selected from R13, heterocycloalkyl substituted with 1 substituent selected from R13, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, phenyl, or substituted phenyl;
Each R11 is independently H, alkyl, cycloalkyl, heterocyclo-alkyl, halogenated alkyl, halogenated cycloalkyl, or halogenated heterocycloalkyl;
R13 is xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR11R11, xe2x80x94C(O)R11, xe2x80x94C(O)NR11R11, xe2x80x94CN, xe2x80x94CF3, xe2x80x94NR11C(O)R11, xe2x80x94S(O)2NR11R11, xe2x80x94NR11S(O)2R11, or xe2x80x94NO2;
R15 is aryl, R7, or R9;
R16 is H, alkyl, substituted alkyl, cycloalkyl, halogenated alkyl, heterocycloalkyl, substituted heterocycloalkyl, substituted phenyl, or substituted naphthyl;
One of R17 is H, alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, xe2x80x94CN, F, Br, Cl, I, xe2x80x94OR1, xe2x80x94C(O)NH2, xe2x80x94NHR1, xe2x80x94SR1, xe2x80x94CO2R1, aryl, R7, or R9, and each of the other two R17 is independently selected from alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, xe2x80x94CN, F, Br, Cl, I, xe2x80x94OR1, xe2x80x94C(O)NH2, xe2x80x94NHR1, xe2x80x94SR1, xe2x80x94CO2R1, aryl, R7, or R9;
Each R18 is independently selected from H, F, Cl, Br, I, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR11R11, xe2x80x94C(O)R11, xe2x80x94NO2, xe2x80x94C(O)NR11R11, xe2x80x94CN, xe2x80x94NR11C(O)R11, xe2x80x94S(O)2NR11R11, or xe2x80x94NR11S(O)2R11, or a bond directly or indirectly attached to the core molecule, provided that there is only one said bond to the core molecule within the 9-membered fused-ring moiety, further provided that the fused-ring moiety has 0-1 substituent selected from alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR11R11, xe2x80x94C(O)R11, xe2x80x94NO2, xe2x80x94C(O)NR11R11, xe2x80x94CN, xe2x80x94NR11C(O)R11, xe2x80x94S(O)2NR11R11, or xe2x80x94NR11S(O)2R11, and further provided that the fused-ring moiety has 0-3 substituent(s) selected from F, Cl, Br, or I;
R19 is H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, phenyl, or phenyl having 1 substituent selected from R20 and further having 0-3 substituents independently selected from F, Cl, Br, or I;
R20 is alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR11R11, xe2x80x94C(O)R11, xe2x80x94C(O)NR11R11, xe2x80x94CN, xe2x80x94NR11C(O)R11, xe2x80x94S(O)2NR11R11, xe2x80x94NR11S(O)2R11, xe2x80x94NO2, alkyl substituted with 1-4 substituent(s) independently selected from F, Cl, Br, I, or R13, cycloalkyl substituted with 1-4 substituent(s) independently selected from F, Cl, Br, I, or R13, or heterocycloalkyl substituted with 1-4 substituent(s) independently selected from F, Cl, Br, I, or R13;
R21 is H, F, Cl, Br, I, alkyl, substituted alkyl, halogenated alkyl, cycloalkyl, xe2x80x94CN, xe2x80x94NR22R22, xe2x80x94OR22, or xe2x80x94SR22;
Each R22 is independently H, alkyl, substituted alkyl, cycloalkyl, halogenated alkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl;
R23 is H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl, substituted phenyl, naphthyl, substituted naphthyl, R7, or R9;
or pharmaceutical composition, pharmaceutically acceptable salt, racemic mixture, or pure enantiomer thereof.
The compounds of Formula I are use to treat any one of or combination of cognitive and attention deficit symptoms of Alzheimer""s, neurodegeneration associated with diseases such as Alzheimer""s disease, pre-senile dementia (mild cognitive impairment), senile dementia, schizophrenia, psychosis, attention deficit disorder, attention deficit hyperactivity disorder, mood and affective disorders, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems associated with brain tumors, AIDS dementia complex, dementia associated with Down""s syndrome, dementia associated with Lewy Bodies, Huntington""s disease, depression, general anxiety disorder, age-related macular degeneration, Parkinson""s disease, tardive dyskinesia, Pick""s disease, post traumatic stress disorder, dysregulation of food intake including bulemia and anorexia nervosa, withdrawal symptoms associated with smoking cessation and dependant drug cessation, Gilles de la Tourette""s Syndrome, glaucoma, neurodegeneration associated with glaucoma, or symptoms associated with pain.
Surprisingly, we have found that compounds of Formula I: 
wherein W0 is a bicyclic moiety and is 
X is O, or S;
R1 is H, alkyl, cycloalkyl, halogenated alkyl, substituted phenyl, or substituted naphthyl;
Alkyl is both straight- and branched-chain moieties having from 1-6 carbon atoms, unless otherwise specified;
Halogenated alkyl is an alkyl moiety having from 1-6 carbon atoms and having 1 to (2n+1) substituent(s) independently selected from F, Cl, Br, or I where n is the maximum number of carbon atoms in the moiety;
Cycloalkyl is a cyclic alkyl moiety having from 3-6 carbon atoms;
Substituted phenyl is a phenyl either having 1-4 substituents independently selected from F, Cl, Br, or I, or having 1 substituent selected from R12 and 0-3 substituents independently selected from F, Cl, Br, or I;
Substituted naphthyl is a naphthalene moiety either having 1-4 substituents independently selected from F, Cl, Br, or I, or having 1 substituent selected from R12 and 0-3 substituents independently selected from F, Cl, Br, or I, where the substitution can be independently on either only one ring or both rings of said naphthalene moiety;
R2 is H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, or aryl;
Aryl is phenyl, substituted phenyl, naphthyl, or substituted naphthyl;
Substituted alkyl is an alkyl moiety from 1-6 carbon atoms and having 0-3 substituents independently selected from F, Cl, Br, or I and further having 1 substituent selected from xe2x80x94OR10, xe2x80x94SR10, xe2x80x94NR10R10, xe2x80x94C(O)R10, xe2x80x94C(O)NR10R10, xe2x80x94CN, xe2x80x94NR10C(O)R10, xe2x80x94S(O)2NR10R10, xe2x80x94NR10S(O)2R10, xe2x80x94NO2, R7, R9, phenyl, or substituted phenyl;
R3 is H, F, alkyl, halogenated alkyl, substituted alkyl, lactam heterocycloalkyl, phenoxy, substituted phenoxy, R7, R9, xe2x80x94N(R4)-aryl, xe2x80x94O-substituted phenyl, xe2x80x94O-substituted naphthyl, xe2x80x94S-substituted phenyl, xe2x80x94S-substituted naphthyl, or alkyl substituted on the xcfx89 carbon with R15 where said xcfx89 carbon is determined by counting the longest carbon chain of the alkyl moiety with the C-1 carbon being the carbon attached to the bicyclic moiety W0 and the xcfx89 carbon being the carbon furthest, e.g., separated by the greatest number of carbon atoms in the chain, from said C-1 carbon;
Lactam heterocycloalkyl is a cyclic moiety having from 4-7 atoms with one atom being only nitrogen with the bond to the lactam heterocycloalkyl thru said atom being only nitrogen and having a xe2x95x90O on a carbon adjacent to said nitrogen, and having up to 1 additional ring atom being oxygen, sulfur, or nitrogen and further having 0-2 substituents selected from F, Cl, Br, I, or R14 where valency allows;
Substituted phenoxy is a phenoxy either having 1-3 substituents independently selected from F, Cl, Br, or I, or having 1 substituent selected from R12 and 0-2 substituents independently selected from F, Cl, Br, or I;
W is C(H) where
Vxe2x80x94Zxe2x80x94Y is selected from Oxe2x80x94C(R3)xe2x95x90N, Oxe2x80x94C(R5)(R3)xe2x80x94N(R4), Oxe2x80x94C(R5)(R3)xe2x80x94S, Oxe2x80x94Nxe2x95x90C(R5), Oxe2x80x94C(R3)(R8)xe2x80x94O, Oxe2x80x94C(R3)(R5)xe2x80x94O, Sxe2x80x94C(R3)xe2x95x90N, Sxe2x80x94C(R5)(R3)xe2x80x94N(R4), Sxe2x80x94Nxe2x95x90C(R5), Nxe2x95x90C(R3)xe2x80x94O, Nxe2x95x90C(R3)xe2x80x94S, Nxe2x95x90C(R3)xe2x80x94N(R4), N(R4)xe2x80x94Nxe2x95x90C(R5), N(R4)xe2x80x94C(R5)(R3)xe2x80x94O, N(R4)xe2x80x94C(R5)(R3)xe2x80x94S, N(R4)xe2x80x94C(R5)(R3)xe2x80x94N(R4), C(R5)2xe2x80x94Oxe2x80x94N(R4), C(R5)2xe2x80x94N(R4)xe2x80x94O, C(R5)2xe2x80x94N(R4)xe2x80x94S, C(R5)xe2x95x90Nxe2x80x94O, C(R5)xe2x95x90Nxe2x80x94S, C(R5)xe2x95x90Nxe2x80x94N(R4), C(R5)2xe2x80x94Oxe2x80x94C(R5)2, C(R5)2xe2x80x94Sxe2x80x94C(R5)2, C(R5)2xe2x80x94N(R4)xe2x80x94C(R5)2, C(R5)(R17)xe2x80x94C(R3)(R17)xe2x80x94C(R5)(R17), or C(R5)2xe2x80x94C(R3)(R5)xe2x80x94C(R5)2;
Q is N(R19), O, or S;
W is N where
Vxe2x80x94Zxe2x80x94Y is selected from Oxe2x80x94C(R3)xe2x95x90N, Oxe2x80x94C(R5)(R3)xe2x80x94N(R4), Oxe2x80x94C(R5)(R3)xe2x80x94S, Oxe2x80x94Nxe2x95x90C(R5) Oxe2x80x94C(R3)(R5)xe2x80x94O, Sxe2x80x94C(R3)xe2x95x90N, Sxe2x80x94C(R5)(R3)xe2x80x94N(R4), Sxe2x80x94Nxe2x95x90C(R5), Nxe2x95x90C(R3)xe2x80x94O, Nxe2x95x90C(R3)xe2x80x94S, Nxe2x95x90C(R3)xe2x80x94N(R4), N(R4)xe2x80x94Nxe2x95x90C(R5), N(R4)xe2x80x94C(R5)(R3)xe2x80x94O, N(R4)xe2x80x94C(R5)(R3)xe2x80x94S, N(R4)xe2x80x94C(R5)(R3)xe2x80x94N(R4), C(R5)2xe2x80x94Oxe2x80x94N(R4), C(R5)2xe2x80x94N(R4)xe2x80x94O, C(R5)2xe2x80x94N(R4)xe2x80x94S, C(R5)xe2x95x90Nxe2x80x94O, C(R5)xe2x95x90Nxe2x80x94S, C(R5)xe2x95x90Nxe2x80x94N(R4), C(R5)xe2x95x90C(R3)xe2x80x94C(R5)2, or C(R5)2xe2x80x94C(R3)(R5)xe2x80x94C(R5)2;
W1, W2, W3, W4 are each independently N or C(R21), provided that no more than two of W1, W2, W3, W4 are N, and further provided when more than two of W1, W2, W3, W4 are C(R21) that no more than two R21 are other than H;
J is N(R23), S, or O;
R4 is H, or alkyl;
R5 is H, F, Br, Cl, I, alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, heterocycloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OR1, xe2x80x94C(O)N(R16)2, xe2x80x94NHR1, xe2x80x94NR1COR16, xe2x80x94N(R10)2, xe2x80x94SR1, xe2x80x94C(O)R16, xe2x80x94CO2R1, aryl, R7, or R9;
Alkenyl is straight- and branched-chain moieties having from 2-6 carbon atoms and having at least one carbon-carbon double bond;
Halogenated alkenyl is an unsaturated alkenyl moiety having from 2-6 carbon atoms and having 1 to (2nxe2x88x921) substituent(s) independently selected from F, Cl, Br, or I where n is the maximum number of carbon atoms in the moiety;
Substituted alkenyl is an unsaturated alkenyl moiety having from 2-6 carbon atoms and having 0-3 substituents independently selected from F, or Cl, and further having 1 substituent selected from xe2x80x94OR10, xe2x80x94SR10, xe2x80x94NR10R10, xe2x80x94C(O)R10, xe2x80x94C(O)NR10R10, xe2x80x94NR10C(O)R10, xe2x80x94S(O)2NR10R10, xe2x80x94NR10S(O)2R10, xe2x80x94CN, R7, R9, phenyl, or substituted phenyl;
Alkynyl is straight- and branched-chained moieties having from 2-6 carbon atoms and having at least one carbon-carbon triple bond;
Halogenated alkynyl is an unsaturated alkynyl moiety having from 3-6 carbon atoms and having 1 to (2nxe2x88x923) substituent(s) independently selected from F, Cl, Br, or I where n is the maximum number of carbon atoms in the moiety;
Substituted alkynyl is an unsaturated alkynyl moiety having from 3-6 carbon atoms and having 0-3 substituents independently selected from F, or Cl, and further having 1 substituent selected from xe2x80x94OR10, xe2x80x94SR10, xe2x80x94NR10R10, xe2x80x94C(O)R10, xe2x80x94C(O)NR10R10, xe2x80x94NR10C(O)R10, xe2x80x94S(O)2NR10R10, xe2x80x94NR10S(O)2R10, xe2x80x94CN, R7, R9, phenyl, or substituted phenyl;
Halogenated cycloalkyl is a cyclic moiety having from 3-6 carbon atoms and having 1-4 substituents independently selected from F, or Cl;
Substituted cycloalkyl is a cyclic moiety having from 3-6 carbon atoms and having 0-3 substituents independently selected from F, or Cl, and further having 1 substituent selected from xe2x80x94OR10, xe2x80x94SR10, xe2x80x94NR10R10, xe2x80x94C(O)R10, xe2x80x94CN, xe2x80x94C(O)NR10R10, xe2x80x94NR10C(O)R10, xe2x80x94S(O)2NR10R10, xe2x80x94NR10S(O)2R10, xe2x80x94NO2, phenyl, or substituted phenyl;
Heterocycloalkyl is a cyclic moiety having 4-7 atoms with 1-2 atoms within the ring being xe2x80x94Sxe2x80x94, xe2x80x94N(R19)xe2x80x94, or xe2x80x94Oxe2x80x94;
Halogenated heterocycloalkyl is a cyclic moiety having from 4-7 atoms with 1-2 atoms within the ring being xe2x80x94Sxe2x80x94, xe2x80x94N(R19)xe2x80x94, or xe2x80x94Oxe2x80x94, and having 1-4 substituents independently selected from F, or Cl;
Substituted heterocycloalkyl is a cyclic moiety having from 4-7 atoms with 1-2 atoms within the ring being xe2x80x94Sxe2x80x94, xe2x80x94N(R19)xe2x80x94, or xe2x80x94Oxe2x80x94 and having 0-3 substituents independently selected from F, or Cl, and further having 1 substituent selected from R7, R9, xe2x80x94OR10, xe2x80x94SR10, xe2x80x94NR10R10, xe2x80x94C(O)R10, xe2x80x94C(O)NR10R10, xe2x80x94CN, xe2x80x94NR10C(O)R10, xe2x80x94NO2, xe2x80x94S(O)2NR10R10, xe2x80x94NR10S(O)2R10, phenyl, or phenyl having 1 substituent selected from R20 and further having 0-3 substituents independently selected from F, Cl, Br, or I;
R6 is H, F, Cl, Br, I, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OR16, xe2x80x94SR16, or xe2x80x94N(R16)2;
R7 is 5-membered heteroaromatic mono-cyclic moieties containing within the ring 1-3 heteroatoms independently selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x95x90Nxe2x80x94, xe2x80x94N(R19)xe2x80x94, and xe2x80x94Sxe2x80x94, and having 0-1 substituent selected from R20 and further having 0-3 substituents independently selected from F, Cl, Br, or I, or R7 is 9-membered fused-ring moieties having a 6-membered ring fused to a 5-membered ring and having the formula 
wherein E is O, S, or NR19, 
wherein E and G are independently selected from CR18, O, S, N, or NR19, and A is CR18 or N, or 
wherein E and G are independently selected from CR18, O, S, N, or NR19, and A is CR18 or N, each 9-membered fused-ring moiety having 0-1 substituent selected from R20 and further having 0-3 substituent(s) independently selected from F, Cl, Br, or I, and having a bond directly or indirectly attached to the core molecule where valency allows in either the 6-membered or the 5-membered ring of the fused-ring moiety;
Each R8 is independently F, Br, Cl, I, alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OR1, xe2x80x94C(O)NH2, xe2x80x94NHR1, xe2x80x94SR1, xe2x80x94CO2R1, aryl, phenoxy, substituted phenoxy, heteroaryl, xe2x80x94N(R4)-aryl, or xe2x80x94O-substituted aryl.
R9 is 6-membered heteroaromatic mono-cyclic moieties containing within the ring 1-3 heteroatoms selected from xe2x95x90Nxe2x80x94 and having 0-1 substituent selected from R20 and 0-3 substituent(s) independently selected from F, Cl, Br, or I, or R9 is 10-membered heteroaromatic bi-cyclic moieties containing within one or both rings 1-3 heteroatoms selected from xe2x95x90Nxe2x80x94, including, but not limited to, quinolinyl or isoquinolinyl, each 10-membered fused-ring moiety having 0-1 substituent selected from R20 and 0-3 substituent(s) independently selected from F, Cl, Br, or I and having a bond directly or indirectly attached to the core molecule where valency allows;
Each R10 is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 substituent selected from R13, cycloalkyl substituted with 1 substituent selected from R13, heterocycloalkyl substituted with 1 substituent selected from R13, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, phenyl, or substituted phenyl;
Each R11 is independently H, alkyl, cycloalkyl, heterocyclo-alkyl, halogenated alkyl, halogenated cycloalkyl, or halogenated heterocycloalkyl;
R12 is xe2x80x94OR11, xe2x80x94SR11, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, xe2x80x94NR11R11, xe2x80x94C(O)R11, xe2x80x94NO2, xe2x80x94C(O)NR11R11, xe2x80x94CN, xe2x80x94NR11C(O)R11, xe2x80x94S(O)2NR11R11, or xe2x80x94NR11S(O)2R11;
R13 is xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR11R11, xe2x80x94C(O)R11, xe2x80x94C(O)NR11R11, xe2x80x94CN, xe2x80x94CF3, xe2x80x94NR11C(O)R11, xe2x80x94S(O)2NR11R11, xe2x80x94NR11S(O)2R11, or xe2x80x94NO2;
R14 is alkyl, substituted alkyl, halogenated alkyl, xe2x80x94OR11, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR10R10;
R15 is aryl, R7, or R9;
R16 is H, alkyl, substituted alkyl, cycloalkyl, halogenated alkyl, heterocycloalkyl, substituted heterocycloalkyl, substituted phenyl, or substituted naphthyl;
One of R17 is H, alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, xe2x80x94CN, F, Br, Cl, I, xe2x80x94OR1, xe2x80x94C(O)NH2, xe2x80x94NHR1, xe2x80x94SR1, xe2x80x94CO2R1, aryl, R7, or R9, and each of the other two R17 is independently selected from alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, xe2x80x94CN, F, Br, Cl, I, xe2x80x94OR1, xe2x80x94C(O)NH2, xe2x80x94NHR1, xe2x80x94SR1, xe2x80x94CO2R1, aryl, R7, or R9;
Each R18 is independently selected from H, F, Cl, Br, I, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR11R11, xe2x80x94C(O)R11, xe2x80x94NO2, xe2x80x94C(O)NR11R11, xe2x80x94CN, xe2x80x94NR11C(O)R11, xe2x80x94S(O)2NR11R11, or xe2x80x94NR11S(O)2R11, or a bond directly or indirectly attached to the core molecule, provided that there is only one said bond to the core molecule within the 9-membered fused-ring moiety, further provided that the fused-ring moiety has 0-1 substituent selected from alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR11R11, xe2x80x94C(O)R11, xe2x80x94NO2, xe2x80x94C(O)NR11R11, xe2x80x94CN, xe2x80x94NR11C(O)R11, xe2x80x94S(O)2NR11R11, or xe2x80x94NR11S(O)2R11, and further provided that the fused-ring moiety has 0-3 substituent(s) selected from F, Cl, Br, or I;
R19 is H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, phenyl, or phenyl having 1 substituent selected from R20 and further having 0-3 substituents independently selected from F, Cl, Br, or I;
R20 is alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR11R11, xe2x80x94C(O)R11, xe2x80x94C(O)NR11R11, xe2x80x94CN, xe2x80x94NR11C(O)R11, xe2x80x94S(O)2NR11R11, xe2x80x94NR11S(O)2R11, xe2x80x94NO2, alkyl substituted with 1-4 substituent(s) independently selected from F, Cl, Br, I, or R13, cycloalkyl substituted with 1-4 substituent(s) independently selected from F, Cl, Br, I, or R13, or heterocycloalkyl substituted with 1-4 substituent(s) independently selected from F, Cl, Br, I, or R13;
R21 is H, F, Cl, Br, I, alkyl, substituted alkyl, halogenated alkyl, cycloalkyl, xe2x80x94CN, xe2x80x94NR22R22, xe2x80x94OR22, or xe2x80x94SR22;
Each R22 is independently H, alkyl, substituted alkyl, cycloalkyl, halogenated alkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl;
R23 is H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl, substituted phenyl, naphthyl, substituted naphthyl, R7, or R9;
or pharmaceutical composition, pharmaceutically acceptable salt, racemic mixture, or pure enantiomer thereof useful to treat any one of or combination of cognitive and attention deficit symptoms of Alzheimer""s, neurodegeneration associated with diseases such as Alzheimer""s disease, pre-senile dementia (mild cognitive impairment), senile dementia, schizophrenia, psychosis, attention deficit disorder, attention deficit hyperactivity disorder, mood and affective disorders, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems associated with brain tumors, AIDS dementia complex, dementia associated with Down""s syndrome, dementia associated with Lewy Bodies, Huntington""s disease, depression, general anxiety disorder, age-related macular degeneration, Parkinson""s disease, tardive dyskinesia, Pick""s disease, post traumatic stress disorder, dysregulation of food intake including bulemia and anorexia nervosa, withdrawal symptoms associated with smoking cessation and dependant drug cessation, Gilles de la Tourette""s Syndrome, glaucoma, neurodegeneration associated with glaucoma, or symptoms associated with pain.
In another aspect, the invention includes methods of treating a mammal suffering from schizophrenia or psychosis by administering compounds of Formula I in conjunction with antipsychotic drugs. The compounds of Formula I and the antipsychotic drugs can be administered simultaneously or at separate intervals. When administered simultaneously the compounds of Formula I and the antipsychotic drugs can be incorporated into a single pharmaceutical composition. Alternatively, two separate compositions, i.e., one containing compounds of Formula I and the other containing antipsychotic drugs, can be administered simultaneously.
The present invention also includes the intermediates, the processes to make them and the compounds of the present invention, pharmaceutical compositions containing the active compounds, and methods to treat the identified diseases.
One group of compounds of Formula I includes compounds having the R configuration at the C3 position of the quinuclidine ring. Another group of compounds of Formula I includes compounds having the S configuration at the C3 position of the quinuclidine ring. Another group of compounds of Formula I includes compounds wherein the quinuclidine has S configuration at C2 when R2 is other than H and at C2. Another group of compounds of Formula I includes compounds wherein the quinuclidine has 2S,3R configuration at C2 when R2 is other than H at C2 with the amide-type bond being at C3.
Another group of compounds of Formula I includes compounds wherein X is O. Another group of compounds of Formula I includes compounds where R1 is H. Another group of compounds of Formula I includes compounds wherein R2 is H. Another group of compounds of Formula I includes compounds wherein R1 is alkyl, cycloalkyl, halogenated alkyl, substituted phenyl, or substituted naphthyl. Another group of compounds of Formula I includes compounds wherein R2 is alkyl. Another group of compounds of Formula I includes compounds wherein R2 is methyl. Another group of compounds of Formula I includes compounds wherein R2 is alkyl, halogenated alkyl, or substituted alkyl. Another group of compounds of Formula I includes compounds wherein R2 is alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, or aryl.
Another group of compounds of Formula I includes compounds wherein W is CH. Another group of compounds of Formula I includes compounds wherein W is CH and wherein Vxe2x80x94Zxe2x80x94Y is Oxe2x80x94C(R3)xe2x95x90N, Oxe2x80x94C(R5)(R3)xe2x80x94N(R4), Oxe2x80x94C(R5)(R3)xe2x80x94S, Oxe2x80x94Nxe2x95x90C(R5), Oxe2x80x94C(R3)(R5)xe2x80x94O, Sxe2x80x94C(R3)xe2x95x90N, Sxe2x80x94C(R5)(R3)xe2x80x94N(R4), Sxe2x80x94Nxe2x95x90C(R5), Nxe2x95x90C(R3)xe2x80x94O, Nxe2x95x90C(R3)xe2x80x94S, Nxe2x95x90C(R3)xe2x80x94N(R4), N(R4)xe2x80x94Nxe2x95x90C(R5), N(R4)xe2x80x94C(R5)(R3)xe2x80x94O, N(R4)xe2x80x94C(R5)(R3)xe2x80x94S, N(R4)xe2x80x94C(R5)(R3)xe2x80x94N(R4), C(R5)2xe2x80x94Oxe2x80x94N(R4), C(R5)2xe2x80x94N(R4)xe2x80x94O, C(R5)2xe2x80x94N(R4)xe2x80x94S, C(R5)xe2x95x90Nxe2x80x94O, C(R5)xe2x95x90Nxe2x80x94S, C(R5)xe2x95x90Nxe2x80x94N(R4), C(R5)2xe2x80x94Oxe2x80x94C(R5)2, C(R5)2xe2x80x94Sxe2x80x94C(R5)2, C(R5)2xe2x80x94N(R4)xe2x80x94C(R5)2, or C(R5)2xe2x80x94C(R3)(R5)xe2x80x94C(R5)2.
Another group of compounds of Formula I includes compounds wherein W is CH and wherein Vxe2x80x94Zxe2x80x94Y is independently any one of or combination of Oxe2x80x94C(R3)xe2x95x90N, Oxe2x80x94C(R5)(R3)xe2x80x94N(R4), Oxe2x80x94C(R5)(R3)xe2x80x94S, Oxe2x80x94Nxe2x95x90C(R5), Oxe2x80x94C(R3)(R5)xe2x80x94O, Sxe2x80x94C(R3)xe2x95x90N, Sxe2x80x94C(R5)(R3)xe2x80x94N(R4), Sxe2x80x94Nxe2x95x90C(R5), Nxe2x95x90C(R3)xe2x80x94O, Nxe2x95x90C(R3)xe2x80x94S, Nxe2x95x90C(R3)xe2x80x94N(R4), N(R4)xe2x80x94Nxe2x95x90C(R5), N(R4)xe2x80x94C(R5)(R3)xe2x80x94O, N(R4)xe2x80x94C(R5)(R3)xe2x80x94S, N(R4)xe2x80x94C(R5)(R3)xe2x80x94N(R4), C(R5)2xe2x80x94Oxe2x80x94N(R4), C(R5)2xe2x80x94N(R4)xe2x80x94O, C(R5)2xe2x80x94N(R4)xe2x80x94S, C(R5)xe2x95x90Nxe2x80x94O, C(R5)xe2x95x90Nxe2x80x94S, C(R5)xe2x95x90Nxe2x80x94N(R4), C(R5)2xe2x80x94Oxe2x80x94C(R5)2, C(R5)2xe2x80x94Sxe2x80x94C(R5)2, C(R5)2xe2x80x94N(R4)xe2x80x94C(R5)2, or C(R5)(R17)xe2x80x94C(R3)(R17)xe2x80x94C(R5)(R17).
Another group of compounds of Formula I includes compounds wherein W is CH and wherein Vxe2x80x94Zxe2x80x94Y is independently any one of or combination of Oxe2x80x94C(R3)xe2x95x90N, Oxe2x80x94C(R5)(R3)xe2x80x94N(R4), Oxe2x80x94C(R5)(R3)xe2x80x94S, Oxe2x80x94Nxe2x95x90C(R5), Oxe2x80x94C(R3)(R8)xe2x80x94O, Sxe2x80x94C(R3)xe2x95x90N, Sxe2x80x94C(R5)(R3)xe2x80x94N(R4), Sxe2x80x94Nxe2x95x90C(R5), Nxe2x95x90C(R3)xe2x80x94O, Nxe2x95x90C(R3)xe2x80x94S, Nxe2x95x90C(R3)xe2x80x94N(R4), N(R4)xe2x80x94Nxe2x95x90C(R5), N(R4)xe2x80x94C(R5)(R3)xe2x80x94O, N(R4)xe2x80x94C(R5)(R3)xe2x80x94S, N(R4)xe2x80x94C(R5)(R3)xe2x80x94N(R4), C(R5)2xe2x80x94Oxe2x80x94N(R4), C(R5)2xe2x80x94N(R4)xe2x80x94O, C(R5)2xe2x80x94N(R4)xe2x80x94S, C(R5)xe2x95x90Nxe2x80x94O, C(R5)xe2x95x90Nxe2x80x94S, C(R5)xe2x95x90Nxe2x80x94N(R4), C(R5)2xe2x80x94Oxe2x80x94C(R5)2, C(R5)2xe2x80x94Sxe2x80x94C(R5)2, C(R5)2xe2x80x94N(R4)xe2x80x94C(R5)2, or C(R5)2xe2x80x94C(R3)(R5)xe2x80x94C(R5)2.
Another group of compounds of Formula I includes compounds wherein W is CH and wherein Vxe2x80x94Zxe2x80x94Y is independently any one of or combination of Oxe2x80x94C(R3)xe2x95x90N, Oxe2x80x94C(R5)(R3)xe2x80x94N(R4), Oxe2x80x94C(R5)(R3)xe2x80x94S, Oxe2x80x94Nxe2x95x90C(R5), Oxe2x80x94C(R3)(R8)xe2x80x94O, Sxe2x80x94C(R3)xe2x95x90N, Sxe2x80x94C(R5)(R3)xe2x80x94N(R4), Sxe2x80x94Nxe2x95x90C(R5), Nxe2x95x90C(R3)xe2x80x94O, Nxe2x95x90C(R3)xe2x80x94S, Nxe2x95x90C(R3)xe2x80x94N(R4), N(R4)xe2x80x94Nxe2x95x90C(R5), N(R4)xe2x80x94C(R5)(R3)xe2x80x94O, N(R4)xe2x80x94C(R5)(R3)xe2x80x94S, N(R4)xe2x80x94C(R5)(R3)xe2x80x94N(R4), C(R5)2xe2x80x94Oxe2x80x94N(R4), C(R5)2xe2x80x94N(R4)xe2x80x94O, C(R5)2xe2x80x94N(R4)xe2x80x94S, C(R5)xe2x95x90Nxe2x80x94O, C(R5)xe2x95x90Nxe2x80x94S, C(R5)xe2x95x90Nxe2x80x94N(R4), C(R5)2xe2x80x94Oxe2x80x94C(R5)2, C(R5)2xe2x80x94Sxe2x80x94C(R5)2, C(R5)2xe2x80x94N(R4)xe2x80x94C(R5)2, or C(R5)(R17)xe2x80x94C(R3)(R17)xe2x80x94C(R5)(R17).
Another group of compounds of Formula I includes compounds wherein W is N. Another group of compounds of Formula I includes compounds wherein W is N and wherein Vxe2x80x94Zxe2x80x94Y is independently any one of or combination of Oxe2x80x94C(R3)xe2x95x90N, Oxe2x80x94C(R5)(R3)xe2x80x94N(R4), Oxe2x80x94C(R5)(R3)xe2x80x94S, Oxe2x80x94Nxe2x95x90C(R5) Oxe2x80x94C(R3)(R5)xe2x80x94O, Sxe2x80x94C(R3)xe2x95x90N, Sxe2x80x94C(R5)(R3)xe2x80x94N(R4), Sxe2x80x94Nxe2x95x90C(R5), Nxe2x95x90C(R3)xe2x80x94O, Nxe2x95x90C(R3)xe2x80x94S, Nxe2x95x90C(R3)xe2x80x94N(R4), N(R4)xe2x80x94Nxe2x95x90C(R5), N(R4)xe2x80x94C(R5)(R3)xe2x80x94O, N(R4)xe2x80x94C(R5)(R3)xe2x80x94S, N(R4)xe2x80x94C(R5)(R3)xe2x80x94N(R4), C(R5)2xe2x80x94Oxe2x80x94N(R4), C(R5)2xe2x80x94N(R4)xe2x80x94O, C(R5)2xe2x80x94N(R4)xe2x80x94S, C(R5)xe2x95x90Nxe2x80x94O, C(R5)xe2x95x90Nxe2x80x94S, C(R5)xe2x95x90Nxe2x80x94N(R4), C(R5)xe2x95x90C(R3)xe2x80x94C(R5)2, or C(R5)2xe2x80x94C(R3)(R5)xe2x80x94C(R5)2.
Another group of compounds of Formula I includes compounds wherein R3 is H, F, alkyl, halogenated alkyl, substituted alkyl, lactam heterocycloalkyl, phenoxy, substituted phenoxy, R7, R9, xe2x80x94N(R4)-aryl, xe2x80x94O-substituted phenyl, xe2x80x94O-substituted naphthyl, xe2x80x94S-substituted phenyl, xe2x80x94S-substituted naphthyl, alkyl substituted on the xcfx89 carbon with naphthyl, or alkyl substituted on the xcfx89 carbon with substituted naphthyl. Said xcfx89 carbon is determined by counting the longest carbon chain of the alkyl moiety with the C-1 carbon being the carbon attached to the bicyclic moiety W0 and the xcfx89 carbon being the carbon furthest, e.g., separated by the greatest number of carbon atoms in the chain, from said C-1 carbon. Another group of compounds of Formula I includes compounds wherein R3 is H, F, alkyl, halogenated alkyl, substituted alkyl, lactam heterocycloalkyl, phenoxy, substituted phenoxy, xe2x80x94N(R4)-aryl, xe2x80x94O-substituted phenyl, xe2x80x94O-substituted naphthyl, xe2x80x94S-substituted phenyl, xe2x80x94S-substituted naphthyl, alkyl substituted on the xcfx89 carbon with naphthyl, or alkyl substituted on the xcfx89 carbon with substituted naphthyl.
Another group of compounds of Formula I includes compounds wherein R3 is H, F, alkyl, halogenated alkyl, lactam heterocycloalkyl, phenoxy, substituted phenoxy, R7, R9, xe2x80x94N(R4)-aryl, xe2x80x94O-substituted phenyl, xe2x80x94O-substituted naphthyl, xe2x80x94S-substituted phenyl, xe2x80x94S-substituted naphthyl, or or alkyl substituted on the xcfx89 carbon with R15.
Another group of compounds of Formula I includes compounds wherein R3 is H, F, alkyl, halogenated alkyl, lactam heterocycloalkyl, phenoxy, substituted phenoxy, xe2x80x94N(R4)-aryl, xe2x80x94O-substituted phenyl, xe2x80x94O-substituted naphthyl, xe2x80x94S-substituted phenyl, xe2x80x94S xe2x80x94substituted naphthyl, or alkyl substituted on the xcfx89 carbon with R15.
Another group of compounds of Formula I includes compounds wherein R5 is H, F, Br, Cl, I, alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, heterocycloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OR1, xe2x80x94C(O)N(R16)2, xe2x80x94NHR1, xe2x80x94NR1COR16, xe2x80x94N(R10)2, xe2x80x94SR1, xe2x80x94C(O)R16, xe2x80x94CO2R1, aryl, R7, or R9. Another group of compounds of Formula I includes compounds wherein R5 is H, F, Br, Cl, alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, heterocycloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OR1, xe2x80x94C(O)N(R16)2, xe2x80x94NHR1, xe2x80x94NR1COR16, xe2x80x94N(R10)2, xe2x80x94SR1. 
Another group of compounds of Formula I includes compounds wherein R6 is any one of or combination of H, F, Cl, Br, I, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OR16, xe2x80x94SR16, or xe2x80x94N(R16)2. Another group of compounds of Formula I includes compounds wherein R6 is any one of or combination of H, F, Cl, Br, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OR16, xe2x80x94SR16, or xe2x80x94N(R16)2.
Another group of compounds of Formula I includes compounds wherein R17 is any one of or combination of H, F, Br, Cl, I, alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, xe2x80x94CN, xe2x80x94OR1, xe2x80x94C(O)NH2, xe2x80x94NHR1, xe2x80x94SR1, xe2x80x94CO2R1, aryl, R7, or R9. Another group of compounds of Formula I includes compounds wherein R17 is any one of or combination of H, F, Br, Cl, alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, xe2x80x94CN, xe2x80x94OR1, xe2x80x94C(O)NH2, xe2x80x94NHR1, xe2x80x94SR1.
Another group of compounds of Formula I includes compounds wherein R21 is any one of or combination of H, F, Cl, Br, I, alkyl, substituted alkyl, halogenated alkyl, cycloalkyl, xe2x80x94CN, xe2x80x94NR22R22, xe2x80x94OR22, or xe2x80x94SR22. Another group of compounds of Formula I includes compounds wherein R21 is any one of or combination of H, F, Cl, Br, alkyl, substituted alkyl, halogenated alkyl, xe2x80x94CN, xe2x80x94N(R22)2, xe2x80x94OR22, or xe2x80x94SR22.
Another group of compounds of Formula I includes compounds wherein R23 is any one of or combination of H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl, substituted phenyl, naphthyl, substituted naphthyl, R7, or R9. Another group of compounds of Formula I includes compounds wherein R23 is any one of or combination of H, alkyl, halogenated alkyl, substituted alkyl, heterocycloalkyl, or substituted heterocycloalkyl.
Another group of compounds of Formula I includes compounds wherein W0 is 
wherein W, R6, and Vxe2x80x94Zxe2x80x94Y are defined herein.
Another group of compounds of Formula I includes compounds wherein W0 is 
wherein Q and R6 are defined herein.
Another group of compounds of Formula I for treating the diseases or conditions discussed herein includes compounds wherein W0 is 
wherein W1, W2, W3, W4 are each independently N or C(R21), provided that no more than two of W1, W2, W3, W4 are N, and further provided when more than two of W1, W2, W3, W4 are C(R21) that no more than two R21 are other than H; and wherein J is N(R23), S, or O.
Another group of compounds of Formula I includes compounds wherein W0 is 
wherein W1, W2, W3, W4 are each independently N or C(R21), provided that no more than two of W1, W2, W3, W4 are N, further provided that when J is N(R23), at least one of W1, W2, W3, W4 is N, and further provided when more than two of W1, W2, W3, W4 are C(R21) that no more than two R21 are other than H; and wherein J is N(R23), S, or O.
Another group of compounds of Formula I includes compounds wherein W0 is 
wherein W1, W2, W3, W4 are each independently N or C(R21), provided that no more than two of W1, W2, W3, W4 are N, and further provided when more than two of W1, W2, W3, W4 are C(R21) that no more than two R21 are other than H; and wherein J is S, or O.
Another group of compounds of Formula I includes compounds wherein W0 includes any one of or combination of the following:
1,3-benzoxazol-6-yl, 1,3-benzoxazol-5-yl, 1,3-benzothiazol-6-yl, indan-5-yl, 1,3-benzodioxol-5-yl, [1,3]oxazolo[5,4-c]pyridin-6-yl, 2-benzoisothiophen-5-yl, 1,3-benzothiazol-5-yl, 1,3-benzothiazol-2-yl, 1,2-benzisoxazol-6-yl, 1,2-benzisoxazol-5-yl, 3H-imidazo[4,5-b]pyridin-2-yl, or 1H-indazol-6-yl, optionally substituted with F, Br, Cl, alkyl, halogenated alkyl, substituted alky, alkyl substituted on the xcfx89 carbon with R15, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, heterocycloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, phenoxy, substituted phenoxy, xe2x80x94CF3, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OR1, xe2x80x94OR16, xe2x80x94OR22, xe2x80x94O-substituted phenyl, xe2x80x94O-substituted naphthyl, xe2x80x94NHR1, xe2x80x94N(R10)2, xe2x80x94N(R16)2, xe2x80x94N(R22)2, xe2x80x94N(R4)-aryl, xe2x80x94SR1, xe2x80x94SR16, xe2x80x94SR22, xe2x80x94S-substituted phenyl, xe2x80x94S-substituted naphthyl, xe2x80x94C(O)N(R16)2, xe2x80x94NR1COR16. One of ordinary skill in the art will recognize where the optional substitution is allowed by comparing the listed moieties with W0 and identifying where R3, R4, R5, R6, R17, R21, and R23 would allow for substitution.
Another group of compounds of Formula I includes any one of or combination of the following:
N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzoxazole-6-carboxamide; N-((3R)1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-1,3-benzoxazole-6-carboxamide; N-((3R)1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzoxazole-5-carboxamide; N-((3R)1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-1,3-benzoxazole-5-carboxamide; N-((3R)1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzothiazole-6-carboxamide; N-((3R)1-azabicyclo[2.2.2]oct-3-yl)indane-5-carboxamide; N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzodioxole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl][1,3]oxazolo[5,4-c]pyridine-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-benzoisothiophene-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1,3-benzothiazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazole-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1,3-benzothiazole-2-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-fluoro-1,3-benzothiazole-2-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamide; N-((2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzoxazole-6-carboxamide; N-((2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-1,3-benzoxazole-6-carboxamide; N-((2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzoxazole-5-carboxamide; N-((2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-1,3-benzoxazole-5-carboxamide; N-((2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzothiazole-6-carboxamide; N-((2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl)indane-5-carboxamide; N-((2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzodioxole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl][1,3]oxazolo[5,4-c]pyridine-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-benzoisothiophene-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-benzothiazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazole-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-benzothiazole-2-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-6-fluoro-1,3-benzothiazole-2-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamide; or a pharmaceutically acceptable salt or pharmaceutical composition thereof.
Another group of compounds of Formula I includes any one of or combination of the following: N-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzoxazole-6-carboxamide; N-((3S)1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-1,3-benzoxazole-6-carboxamide; N-((3S)1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzoxazole-5-carboxamide; N-((3S)1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-1,3-benzoxazole-5-carboxamide; N-((3S)1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzothiazole-6-carboxamide; N-((3S)1azabicyclo[2.2.2]oct-3-yl)indane-5-carboxamide; N-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzodioxole-5-carboxamide; N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl][1,3]oxazolo[5,4-c]pyridine-6-carboxamide; N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-2-benzoisothiophene-5-carboxamide N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,3-benzothiazole-5-carboxamide; N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazole-6-carboxamide; N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazole-5-carboxamide; N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-6-carboxamide; N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,3-benzothiazole-2-carboxamide; N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-fluoro-1,3-benzothiazole-2-carboxamide; N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamide; or a pharmaceutically acceptable salt or pharmaceutical composition thereof.
Another group of compounds of Formula I includes any one of or combination of the following: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1H-indazole-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1H-indazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1H-indazole-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1H-indazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1,2-benzisothiazole-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1,2-benzisothiazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisothiazole-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisothiazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-cyclopropyl-1,3-benzoxazole-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-cyclopropyl-1,3-benzoxazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-cyclopropyl-1,3-benzothiazole-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-cyclopropyl-1,3-benzothiazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1,3-benzothiazole-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1,3-benzothiazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-ethyl-1,3-benzothiazole-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-ethyl-1,3-benzothiazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1,3-benzodioxole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-ethyl-1,3-benzodioxole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2,2-dimethyl-1,3-benzodioxole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-benzofuran-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2H-isoindole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-benzimidazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl][1,3]thiazolo[5,4-c]pyridine-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl][1,3]thiazolo[4,5-c]pyridine-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl][1,3]dioxolo[4,5-c]pyridine-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl][1,3]oxazolo[4,5-c]pyridine-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-imidazo[4,5-c]pyridine-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1H-indazole-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1H-indazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1H-indazole-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1H-indazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1,2-benzisothiazole-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1,2-benzisothiazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisothiazole-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisothiazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-cyclopropyl-1,3-benzoxazole-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-cyclopropyl-1,3-benzoxazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-cyclopropyl-1,3-benzothiazole-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-cyclopropyl-1,3-benziothiazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1,3-benzothiazole-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1,3-benzothiazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-ethyl-1,3-benzothiazole-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-ethyl-1,3-benzothiazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1,3-benzodioxole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-ethyl-1,3-benzodioxole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2,2-dimethyl-1,3-benzodioxole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-benzofuran-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2H-isoindole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1H-benzimidazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl][1,3]thiazolo[5,4-c]pyridine-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl][1,3]thiazolo[4,5-c]pyridine-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl][1,3]dioxolo[4,5-c]pyridine-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl][1,3]oxazolo[4,5-c]pyridine-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1H-imidazo[4,5-c]pyridine-6-carboxamide; or a pharmaceutically acceptable salt or pharmaceutical composition thereof.
Abbreviations which are well known to one of ordinary skill in the art may be used (e.g., xe2x80x9cPhxe2x80x9d for phenyl, xe2x80x9cMexe2x80x9d for methyl, xe2x80x9cEtxe2x80x9d for ethyl, xe2x80x9chxe2x80x9d or xe2x80x9chrxe2x80x9d for hour or hours, min for minute or minutes, and xe2x80x9crtxe2x80x9d or xe2x80x9cRTxe2x80x9d for room temperature).
All temperatures are in degrees Centigrade.
Room temperature is within the range of 15-25 degrees Celsius.
AChR refers to acetylcholine receptor.
nAChR refers to nicotinic acetylcholine receptor.
Pre-senile dementia is also known as mild cognitive impairment.
5HT3R refers to the serotonin-type 3 receptor.
xcex1-btx refers to xcex1-bungarotoxin.
FLIPR refers to a device marketed by Molecular Devices, Inc. designed to precisely measure cellular fluorescence in a high throughput whole-cell assay. (Schroeder et. al., J. Biomolecular Screening, 1(2), p 75-80, 1996).
TLC refers to thin-layer chromatography.
HPLC refers to high pressure liquid chromatography.
MeOH refers to methanol.
EtOH refers to ethanol.
IPA refers to isopropyl alcohol.
THF refers to tetrahydrofuran.
DMSO refers to dimethylsulfoxide.
DMF refers to N,N-dimethylformamide.
EtOAc refers to ethyl acetate.
TMS refers to tetramethylsilane.
TEA refers to triethylamine.
DIEA refers to N,N-diisopropylethylamine.
MLA refers to methyllycaconitine.
Ether refers to diethyl ether.
HATU refers to O-(7-azabenzotriazol-1-yl)-N,N,Nxe2x80x2, Nxe2x80x2-tetramethyluronium hexafluorophosphate.
CDI refers to carbonyl diimidazole.
NMO refers to N-methylmorpholine-N-oxide.
TPAP refers to tetrapropylammonium perruthenate.
Halogen is F, Cl, Br, or I.
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Ci-j indicates a moiety of the integer xe2x80x9cixe2x80x9d to the integer xe2x80x9cjxe2x80x9d carbon atoms, inclusive. Thus, for example, C1-6 alkyl refers to alkyl of one to six carbon atoms.
Non-inclusive examples of heteroaryl compounds that fall within the definition of R7 and R9 include, but are not limited to, thienyl, benzothienyl, pyridyl, thiazolyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl, benzoxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, pyrrolyl, isoquinolinyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pydridazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthridinyl, and furopyridinyl.
Non-inclusive examples of heterocycloalkyl include, but are not limited to, tetrahydrofurano, tetrahydropyrano, morpholino, pyrrolidino, piperidino, piperazine, azetidino, azetidinono, oxindolo, dihydroimidazolo, and pyrrolidinono.
The xcfx89 carbon with R15 is determined by counting the longest carbon chain of the alkyl moiety with the C-1 carbon being the carbon attached to the bicyclic moiety W0 and the xcfx89 carbon being the carbon furthest, e.g., separated by the greatest number of carbon atoms in the chain, from said C-1 carbon.
The core molecule is the quinuclidinyl-(carboxamide-type moiety)-W0: 
Therefore, when determining the xcfx89 carbon, the C-1 carbon will be the carbon attached, as valency allows, to the W0 moiety of the core molecule and the xcfx89 carbon will be the carbon furthest from said C-1 carbon.
Mammal denotes human and other mammals.
Brine refers to an aqueous saturated sodium chloride solution.
Equ means molar equivalents.
IR refers to infrared spectroscopy.
Lv refers to leaving groups within a molecule, including Cl, OH, or mixed anhydride.
NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported in ppm (xcex4) downfield from TMS.
MS refers to mass spectrometry expressed as m/e or mass/charge unit. HRMS refers to high resolution mass spectrometry expressed as m/e or mass/charge unit. M+H+ refers to the positive ion of a parent plus a hydrogen atom. Mxe2x88x92Hxe2x88x92 refers to the negative ion of a parent minus a hydrogen atom. M+Na+ refers to the positive ion of a parent plus a sodium atom. M+K+ refers to the positive ion of a parent plus a potassium atom. EI refers to electron impact. ESI refers to electrospray ionization. CT refers to chemical ionization. FAB refers to fast atom bombardment.
Compounds of the present invention may be in the form of pharmaceutically acceptable salts. The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases, and salts prepared from inorganic acids, and organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, ferric, ferrous, lithium, magnesium, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylamino-ethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, and the like. Salts derived from inorganic acids include salts of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, phosphorous acid and the like. Salts derived from pharmaceutically acceptable organic non-toxic acids include salts of C1-6 alkyl carboxylic acids, di-carboxylic acids, and tri-carboxylic acids such as acetic acid, propionic acid, fumaric acid, succinic acid, tartaric acid, maleic acid, adipic acid, and citric acid, and aryl and alkyl sulfonic acids such as toluene sulfonic acids and the like.
By the term xe2x80x9ceffective amountxe2x80x9d of a compound as provided herein is meant a nontoxic but sufficient amount of the compound(s) to provide the desired effect. As pointed out below, the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease that is being treated, the particular compound(s) used, the mode of administration, and the like. Thus, it is not possible to specify an exact xe2x80x9ceffective amount.xe2x80x9d However, an appropriate effective amount may be determined by one of ordinary skill in the art using only routine experimentation.
The compounds of Formula I have optically active center(s) on the quinuclidine ring. Although it is desirable that the stereochemical purity be as high as possible, absolute purity is not required. This invention involves racemic mixtures and compositions of varying degrees of stereochemical purities. It is preferred to carry out stereoselective syntheses and/or to subject the reaction product to appropriate purification steps so as to produce substantially optically pure materials. Suitable stereoselective synthetic procedures for producing optically pure materials are well known in the art, as are procedures for purifying racemic mixtures into optically pure fractions.
The amount of therapeutically effective compound(s) that is administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound(s) employed, and thus may vary widely. The compositions contain well know carriers and excipients in addition to a therapeutically effective amount of compounds of Formula I. The pharmaceutical compositions may contain active ingredient in the range of about 0.001 to 100 mg/kg/day for an adult, preferably in the range of about 0.1 to 50 mg/kg/day for an adult. A total daily dose of about 1 to 1000 mg of active ingredient may be appropriate for an adult. The daily dose can be administered in one to four doses per day.
In addition to the compound(s) of Formula I, the composition for therapeutic use may also comprise one or more non-toxic, pharmaceutically acceptable carrier materials or excipients. The term xe2x80x9ccarrierxe2x80x9d material or xe2x80x9cexcipientxe2x80x9d herein means any substance, not itself a therapeutic agent, used as a carrier and/or diluent and/or adjuvant, or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition into a discrete article such as a capsule or tablet suitable for oral administration. Excipients can include, by way of illustration and not limitation, diluents, disintegrants, binding agents, adhesives, wetting agents, polymers, lubricants, glidants, substances added to mask or counteract a disagreeable taste or odor, flavors, dyes, fragrances, and substances added to improve appearance of the composition. Acceptable excipients include lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinyl-pyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropyl-methyl cellulose, or other methods known to those skilled in the art. For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. If desired, other active ingredients may be included in the composition.
In addition to the oral dosing, noted above, the compositions of the present invention may be administered by any suitable route, in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compositions may, for example, be administered parenterally, e.g., intravascularly, intraperitoneally, subcutaneously, or intramuscularly. For parenteral administration, saline solution, dextrose solution, or water may be used as a suitable carrier. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, EtOH, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
The serotonin type 3 receptor (5HT3R) is a member of a superfamily of ligand-gated ion channels, which includes the muscle and neuronal nAChR, the glycine receptor, and the xcex3-aminobutyric acid type A receptor. Like the other members of this receptor superfamily, the 5HT3R exhibits a large degree of sequence homology with xcex1 7 nAChR but functionally the two ligand-gated ion channels are very different. For example, xcex17 nAChR is rapidly inactivated, is highly permeable to calcium and is activated by acetylcholine and nicotine. On the other hand, 5HT3R is inactivated slowly, is relatively impermeable to calcium and is activated by serotonin. These experiments suggest that the xcex17 nAChR and 5HT3R proteins have some degree of homology, but function very differently. Indeed the pharmacology of the channels is very different. For example, Ondansetron, a highly selective 5HT3R antagonist, has little activity at the xcex17 nAChR. The converse is also true. For example, GTS-21, a highly selective xcex17 nAChR agonist, has little activity at the 5HT3R.
xcex17 nAChR is a ligand-gated Ca++ channel formed by a homopentamer of xcex17 subunits. Previous studies have established that xcex1-bungarotoxin (xcex1-btx) binds selectively to this homopetameric, xcex17 nAChR subtype, and that xcex17 nAChR has a high affinity binding site for both (xcex1-btx and methyllycaconitine (MLA). xcex17 nAChR is expressed at high levels in the hippocampus, ventral tegmental area and ascending cholinergic projections from nucleus basilis to thalamocortical areas. xcex17 nAChR agonists increase neurotransmitter release, and increase cognition, arousal, attention, learning and memory.
Data from human and animal pharmacological studies establish that nicotinic cholinergic neuronal pathways control many important aspects of cognitive function including attention, learning and memory (Levin, E. D., Psychopharmacology, 108:417-31, 1992; Levin, E. D. and Simon B. B., Psychopharmacology, 138:217-30, 1998). For example, it is well known that nicotine increases cognition and attention in humans. ABT-418, a compound that activates xcex14xcex22 and xcex17 nAChR, improves cognition and attention in clinical trials of Alzheimer""s disease and attention-deficit disorders (Potter, A. et. al., Psychopharmacology (Berl)., 142(4):334-42, March 1999; Wilens, T. E. et. al., Am. J. Psychiatry, 156(12):1931-7, December 1999). It is also clear that nicotine and selective but weak xcex17 nAChR agonists increase cognition and attention in rodents and non-human primates.
Schizophrenia is a complex multifactorial illness caused by genetic and non-genetic risk factors that produce a constellation of positive and negative symptoms. The positive symptoms include delusions and hallucinations and the negative symptoms include deficits in affect, attention, cognition and information processing. No single biological element has emerged as a dominant pathogenic factor in this disease. Indeed, it is likely that schizophrenia is a syndrome that is produced by the combination of many low penetrance risk factors. Pharmacological studies established that dopamine receptor antagonists are efficacious in treating the overt psychotic features (positive symptoms) of schizophrenia such as hallucinations and delusions. Clozapine, an xe2x80x9ca typicalxe2x80x9d antipsychotic drug, is novel because it is effective in treating both the positive and some of the negative symptoms of this disease. Clozapine""s utility as a drug is greatly limited because continued use leads to an increased risk of agranulocytosis and seizure. No other antipsychotic drug is effective in treating the negative symptoms of schizophrenia. This is significant because the restoration of cognitive functioning is the best predictor of a successful clinical and functional outcome of schizophrenic patients (Green, M. F., Am J Psychiatry, 153:321-30, 1996). By extension, it is clear that better drugs are needed to treat the cognitive disorders of schizophrenia in order to restore a better state of mental health to patients with this disorder.
One aspect of the cognitive deficit of schizophrenia can be measured by using the auditory event-related potential (P50) test of sensory gating. In this test, electroencepholographic (EEG) recordings of neuronal activity of the hippocampus are used to measure the subject""s response to a series of auditory xe2x80x9cclicksxe2x80x9d (Adler, L. E. et. al., Biol. Psychiatry, 46:8-18, 1999). Normal individuals respond to the first click with greater degree than to the second click. In general, schizophrenics and schizotypal patients respond to both clicks nearly the same (Cullum, C. M. et. al., Schizophr. Res., 10:131-41, 1993). These data reflect a schizophrenic""s inability to xe2x80x9cfilterxe2x80x9d or ignore unimportant information. The sensory gating deficit appears to be one of the key pathological features of this disease (Cadenhead, K. S. et. al., Am. J. Psychiatry, 157:55-9, 2000). Multiple studies show that nicotine normalizes the sensory deficit of schizophrenia (Adler, L. E. et. al., Am. J. Psychiatry, 150:1856-61, 1993). Pharmacological studies indicate that nicotine""s effect on sensory gating is via the xcex17 nAChR (Adler, L. E. et. al., Schizophr. Bull., 24:189-202, 1998). Indeed, the biochemical data indicate that schizophrenics have 50% fewer of xcex17 nAChR receptors in the hippocampus, thus giving a rationale to partial loss of xcex17 nAChR functionality (Freedman, R. et. al., Biol. Psychiatry, 38:22-33, 1995). Interestingly, genetic data indicate that a polymorphism in the promoter region of the xcex17 nAChR gene is strongly associated with the sensory gating deficit in schizophrenia (Freedman, R. et. al., Proc. Nat""l Acad. Sci. USA, 94(2):587-92, 1997; Myles-Worsley, M. et. al., Am. J. Med. Genet, 88(5):544-50, 1999). To date, no mutation in the coding region of the xcex17 nAChR has been identified. Thus, schizophrenics express the same xcex17 nAChR as non-schizophrenics.
Selective xcex17 nAChR agonists may be found using a functional assay on FLIPR (see WO 00/73431 A2). FLIPR is designed to read the fluorescent signal from each well of a 96 or 384 well plate as fast as twice a second for up to 30 minutes. This assay may be used to accurately measure the functional pharmacology of xcex17 nAChR and 5HT3R. To conduct such an assay, one uses cell lines that expressed functional forms of the xcex17 nAChR using the xcex17/5-HT3 channel as the drug target and cell lines that expressed functional 5HT3R. In both cases, the ligand-gated ion channel was expressed in SH-EP1 cells. Both ion channels can produce robust signal in the FLIPR assay.
The compounds of the present invention are xcex17 nAChR agonists and may be used to treat a wide variety of diseases. For example, they may be used in treating schizophrenia, or psychosis.
Schizophrenia is a disease having multiple aspects. Currently available drugs are generally aimed at controlling the positive aspects of schizophrenia, such as delusions. One drug, Clozapine, is aimed at a broader spectrum of symptoms associated with schizophrenia. This drug has many side effects and is thus not suitable for many patients. Thus, there is a need for a drug to treat the cognitive and attention deficits associated with schizophrenia. Similarly, there is a need for a drug to treat the cognitive and attention deficits associated with schizoaffective disorders, or similar symptoms found in the relatives of schizophrenic patients.
Psychosis is a mental disorder characterized by gross impairment in the patient""s perception of reality. The patient may suffer from delusions, and hallucinations, and may be incoherent in speech. His behavior may be agitated and is often incomprehensible to those around him. In the past, the term psychosis has been applied to many conditions that do not meet the stricter definition given above. For example, mood disorders were named as psychoses.
There are a variety of antipsychotic drugs. The conventional antipsychotic drugs include Chlorpromazine, Fluphenazine, Haloperidol, Loxapine, Mesoridazine, Molindone, Perphenazine, Pimozide, Thioridazine, Thiothixene, and Trifluoperazine. These drugs all have an affinity for the dopamine 2 receptor.
These conventional antipsychotic drugs have several side effects, including sedation, weight gain, tremors, elevated prolactin levels, akathisia (motor restlessness), dystonia and muscle stiffness. These drugs may also cause tardive dyskinesia. Unfortunately, only about 70% of patients with schizophrenia respond to conventional antipsychotic drugs. For these patients, a typical antipsychotic drugs are available.
Atypical antipsychotic drugs generally are able to alleviate positive symptoms of psychosis while also improving negative symptoms of the psychosis to a greater degree than conventional antipsychotics. These drugs may improve neurocognitive deficits. Extrapyramidal (motor) side effects are not as likely to occur with the a typical antipsychotic drugs, and thus, these a typical antipsychotic drugs have a lower risk of producing tardive dyskinesia. Finally these a typical antipsychotic drugs cause little or no elevation of prolactin. Unfortunately, these drugs are not free of side effects. Although these drugs each produce different side effects, as a group the side effects include: agranulocytosis; increased risk of seizures, weight gain, somnolence, dizziness, tachycardia, decreased ejaculatory volume, and mild prolongation of QTc interval.
In a combination therapy to treat multiple symptoms of diseases such as schizophrenia, the compounds of Formula I and the anti-psychotic drugs can be administered simultaneously or at separate intervals. When administered simultaneously the compounds of Formula I and the anti-psychotic drugs can be incorporated into a single pharmaceutical composition, e.g., a pharmaceutical combination therapy composition. Alternatively, two separate compositions, i.e., one containing compounds of Formula I and the other containing anti-psychotic drugs, can be administered simultaneously. Examples of anti-psychotic drugs, in addition to those listed above, include, but are not limited to, Thorazine, Mellaril, Trilafon, Navane, Stelazine, Permitil, Prolixin, Risperdal, Zyprexa, Seroquel, ZELDOX, Acetophenazine, Carphenazine, Chlorprothixene, Droperidol, Loxapine, Mesoridazine, Molindone, Ondansetron, Pimozide, Prochlorperazine, and Promazine.
A pharmaceutical combination therapy composition can include therapeutically effective amounts of the compounds of Formula I, noted above, and a therapeutically effective amount of anti-psychotic drugs. These compositions may be formulated with common excipients, diluents or carriers, and compressed into tablets, or formulated elixirs or solutions for convenient oral administration or administered by intramuscular intravenous routes. The compounds can be administered rectally, topically, orally, sublingually, or parenterally and maybe formulated as sustained relief dosage forms and the like.
When separately administered, therapeutically effective amounts of compositions containing compounds of Formula I and anti-psychotic drugs are administered on a different schedule. One may be administered before the other as long as the time between the two administrations falls within a therapeutically effective interval. A therapeutically effective interval is a period of time beginning when one of either (a) the compounds of Formula I, or (b) the anti-psychotic drugs is administered to a human and ending at the limit of the beneficial effect in the treatment of schizophrenia or psychosis of the combination of (a) and (b). The methods of administration of the compounds of Formula I and the anti-psychotic drugs may vary. Thus, either agent or both agents may be administered rectally, topically, orally, sublingually, or parenterally.
As discussed, the compounds of the present invention are xcex17 nAChR agonists. Therefore, as another aspect of the present invention, the compounds of the present invention may be used to treat a variety of diseases including cognitive and attention deficit symptoms of Alzheimer""s, neurodegeneration associated with diseases such as Alzheimer""s disease, pre-senile dementia (also known as mild cognitive impairment), and senile dementia.
Alzheimer""s disease has many aspects, including cognitive and attention deficits. Currently, these deficits are treated with cholinesterase inhibitors. These inhibitors slow the break down of acetylcholine, and thereby provide a general nonspecific increase in the activity of the cholinergic nervous system. Since the drugs are nonspecific, they have a wide variety of side effects. Thus, there is a need for a drug that stimulates a portion of the cholinergic pathways and thereby provides improvement in the cognitive and attention deficits associated with Alzheimer""s disease without the side effects created by nonspecific stimulation of the cholinergic pathways.
Neurodegeneration is a common problem associated with diseases such as Alzheimer""s disease. While the current drugs treat some of the symptoms of this disease, they do not control the underlying pathology of the disease. Accordingly, it would be desirable to provide a drug that can slow the progress of Alzheimer""s disease.
Pre-senile dementia (mild cognitive impairment) concerns memory impairment rather than attention deficit problems and otherwise unimpaired cognitive functioning. Mild cognitive impairment is distinguished from senile dementia in that mild cognitive impairment involves a more persistent and troublesome problem of memory loss for the age of the patient. There currently is no medication specifically identified for treatment of mild cognitive impairment, due somewhat to the newness of identifying the disease. Therefore, there is a need for a drug to treat the memory problems associated with mild cognitive impairment.
Senile dementia is not a single disease state. However, the conditions classified under this name frequently include cognitive and attention deficits. Generally, these deficits are not treated. Accordingly, there is a need for a drug that provides improvement in the cognitive and attention deficits associated with senile dementia.
As discussed, the compounds of the present invention are xcex17 nAChR agonists. Therefore, yet other diseases to be treated with compounds of the present invention include treating the cognitive and attention deficits as well as the neurodegeneration associated with attention deficit disorder, attention deficit hyperactivity disorder, mood and affective disorders, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems associated with brain tumors, AIDS dementia complex, dementia associated with Down""s syndrome, dementia associated with Lewy Bodies, Huntington""s disease, depression, general anxiety disorder, age-related macular degeneration, Parkinson""s disease, tardive dyskinesia, Pick""s disease, post traumatic stress disorder, dysregulation of food intake including bulemia and anorexia nervosa, withdrawal symptoms associated with smoking cessation and dependant drug cessation, Gilles de la Tourette""s Syndrome, glaucoma, or symptoms associated with pain.
Attention deficit disorder is generally treated with methylphenidate, an amphetamine-like molecule that has some potential for abuse. Accordingly, it would be desirable to provide a drug that treats attention deficit disorder while having fewer side effects than the currently used drug.
Attention deficit hyperactivity disorder, otherwise known as ADHD, is a neurobehavioral disorder affecting 3-5% of all American children. ADHD concerns cognitive alone or both cognitive and behavioral actions by interfering with a person""s ability to stay on a task and to exercise age-appropriate inhibition. Several types of ADHD exist: a predominantly inattentive subtype, a predominantly hyperactive-impulsive subtype, and a combined subtype. Treatment may include medications such as methylphenidate, dextroamphetamine, or pemoline, which act to decrease impulsivity and hyperactivity and to increase attention. No xe2x80x9ccurexe2x80x9d for ADHD currently exists. Children with the disorder seldom outgrow it; therefore, there is a need for appropriate medicaments.
Mood and affective disorders fall within a large group of diseases, including monopolar depression and bi-polar mood disorder. These diseases are treated with three major classes of compounds. The first group is the heterocyclic antidepressant (HCA""s). This group includes the well-known tricyclic antidepressants. The second group of compounds used to treat mood disorders is the monoamine oxidase inhibitors (MAOI""s) that are used in particular types of diseases. The third drug is lithium. Common side effects from HCA""s are sedation and weight gain. In elderly patients with organic brain disease, the side effects of HCA""s can also include seizures and behavioral symptoms. The main side effects from using MAOI""s occur from dietary and drug interactions. Benign side effects from the use of lithium include, but are not limited to, weight gain, nausea, diarrhea, polyuria, polydipsia, and tremor. Toxic side effects from lithium can include persistent headache, mental confusion, and may reach seizures and cardiac arrhythmias. Therefore, agents with less side effects or interactions with food or other medications would be useful.
Depression is a mood disorder of varying lengths of normally several months to more than two years and of varying degrees of feelings involving sadness, despair, and discouragement. The heterocyclic antidepressants (HCA""s) are currently the largest class of antidepressants, but monoamine oxidase inhibitors (MAOI""s) are used in particular types of depression. Common side effects from HCA""s are sedation and weight gain. In elderly patients with organic brain disease, the side effects from HCA""s can also include seizures and behavioral symptoms. The main side effects from using MAOI""s occur from dietary and drug interactions. Therefore, agents with fewer side effects would be useful.
Borderline personality disorder, although not as well known as bipolar disorder, is more common. People having borderline personality disorder suffer from a disorder of emotion regulation. Pharmaceutical agents are used to treat specific symptoms, such as depression or thinking distortions.
Acquired immune deficiency syndrome (AIDS) results from an infection with the human immunodeficiency virus (HIV). This virus attacks selected cells and impairs the proper function of the immune, nervous, and other systems. HIV infection can cause other problems such as, but not limited to, difficulties in thinking, otherwise known as AIDS dementia complex. Therefore, there is a need to drugs to relieve the confusion and mental decline of persons with AIDS.
Amyotrophic lateral sclerosis, also known as Lou Gehrig""s disease, belongs to a class of disorders known as motor neuron diseases wherein specific nerve cells in the brain and spinal cord gradually degenerate to negatively affect the control of voluntary movement. Currently, there is no cure for amyotrophic lateral sclerosis although patients may receive treatment from some of their symptoms and although Riluzole has been shown to prolong the survival of patients. Therefore, there is a need for a pharmaceutical agent to treat this disease.
Traumatic brain injury occurs when the brain is damaged from a sudden physical assault on the head. Symptoms of the traumatic brain injury include confusion and other cognitive problems. Therefore, there is a need to address the symptoms of confusion and other cognitive problems.
Brain tumors are abnormal growths of tissue found inside of the skull. Symptoms of brain tumors include behavioral and cognitive problems. Surgery, radiation, and chemotherapy are used to treat the tumor, but other agents are necessary to address associated symptoms. Therefore, there is a need to address the symptoms of behavioral and cognitive problems.
Persons with Down""s syndrome have in all or at least some of their cells an extra, critical portion of the number 21 chromosome. Adults who have Down""s syndrome are known to be at risk for Alzheimer-type dementia. Currently, there is no proven treatment for Down""s syndrome. Therefore, there is a need to address the dementia associated with Down""s syndrome.
Genetically programmed degeneration of neurons in certain areas of the brain cause Huntington""s disease. Early symptoms of Huntington""s disease include mood swings, or trouble learning new things or remembering a fact. Most drugs used to treat the symptoms of Huntington""s disease have side effects such as fatigue, restlessness, or hyperexcitability. Currently, there is no treatment to stop or reverse the progression of Huntington""s disease. Therefore, there is a need of a pharmaceutical agent to address the symptoms with fewer side effects.
General anxiety disorder (GAD) occurs when a person worries about things such as family, health, or work when there is no reason to worry and is unable not to worry. About 3 to 4% of the U.S. population has GAD during the course of a year. GAD most often strikes people in childhood or adolescence, but can begin in adulthood, too. It affects women more often than men. Currently, treatment involves cognitive-behavioral therapy, relaxation techniques, and biofeedback to control muscle tension and medications such as benzodiazepines, imipramine, and buspirone. These drugs are effective but all have side-effect liabilities. Therefore, there is a need of a pharmaceutical agent to address the symptoms with fewer side effects.
Dementia with Lewy Bodies is a neurodegenerative disorder involving abnormal structures known as Lewy bodies found in certain areas of the brain. Symptoms of dementia with Lewy bodies include, but are not limited to, fluctuating cognitive impairment with episodic delirium. Currently, treatment concerns addressing the parkinsonian and psychiatric symptoms. However, medicine to control tremors or loss of muscle movement may actually accentuate the underlying disease of dementia with Lewy bodies. Therefore, there is a need of a pharmaceutical agent to treat dementia with Lewy bodies.
Age-related macular degeneration (AMD) is a common eye disease of the macula which is a tiny area in the retina that helps produce sharp, central vision required for xe2x80x9cstraight aheadxe2x80x9d activities that include reading and driving. Persons with AMD lose their clear, central vision. AMD takes two forms: wet and dry. In dry AMD, there is a slow breakdown of light-sensing cells in the macula. There currently is no cure for dry AMD. In wet AMD, new, fragile blood vessels growing beneath the macula as dry AMD worsens and these vessels often leak blood and fluid to cause rapid damage to the macula quickly leading to the loss of central vision. Laser surgery can treat some cases of wet AMD. Therefore, there is a need of a pharmaceutical agent to address AMD.
Parkinson""s disease is a neurological disorder characterized by tremor, hypokinesia, and muscular rigidity. Currently, there is no treatment to stop the progression of the disease. Therefore, there is a need of a pharmaceutical agent to address Parkinson""s.
Tardive dyskinesia is associated with the use of conventional antipsychotic drugs. This disease is characterized by involuntary movements most often manifested by puckering of the lips and tongue and/or writhing of the arms or legs. The incidence of tardive dyskinesia is about 5% per year of drug exposure among patients taking conventional antipsychotic drugs. In about 2% of persons with the disease, tardive dyskinesia is severely disfiguring. Currently, there is no generalized treatment for tardive dyskinesia. Furthermore, the removal of the effect-causing drugs is not always an option due to underlying problems. Therefore, there is a need for a pharmaceutical agent to address the symptoms of tardive dyskinesia.
Pick""s disease results from a slowly progressive deterioration of social skills and changes in personality with the resulting symptoms being impairment of intellect, memory, and language. Common symptoms include memory loss, lack of spontaneity, difficulty in thinking or concentrating, and speech disturbances. Currently, there is no specific treatment or cure for Pick""s disease but some symptoms can be treated with cholinergic and serotonin-boosting antidepressants. In addition, antipsychotic medications may alleviate symptoms in FTD patients who are experiencing delusions or hallucinations. Therefore, there is a need for a pharmaceutical agent to treat the progressive deterioration of social skills and changes in personality and to address the symptoms with fewer side effects.
Post-traumatic stress disorder (PTSD) is a form of anxiety triggered by memories of a traumatic event that directly affected the patient or that the patient may have witnessed. The disorder commonly affects survivors of traumatic events including sexual assault, physical assault, war, torture, natural disasters, an automobile accident, an airplane crash, a hostage situation, or a death camp. The affliction also can affect rescue workers at an airplane crash or a mass shooting, someone who witnessed a tragic accident or someone who has unexpectedly lost a loved one. Treatment for PTSD includes cognitive-behavioral therapy, group psychotherapy, and medications such as Clonazepam, Lorazepam and selective serotonin-reuptake inhibitors such as Fluoxetine, Sertraline, Paroxetine, Citalopram and Fluvoxamine. These medications help control anxiety as well as depression. Various forms of exposure therapy (such as systemic desensitization and imaginal flooding) have all been used with PTSD patients. Exposure treatment for PTSD involves repeated reliving of the trauma, under controlled conditions, with the aim of facilitating the processing of the trauma. Therefore, there is a need for better pharmaceutical agents to treat Post traumatic stress disorder.
Dysregulation of food intake associated with eating disease, including bulemia nervosa and anorexia nervosa, involve neurophysiological pathways. Anorexia nervosa is hard to treat due to patients not entering or remaining in after entering programs. Currently, there is no effective treatment for persons suffering from severe anorexia nervosa. Cognitive behavioral therapy has helped patients suffering from bulemia nervosa; however, the response rate is only about 50% and current treatment does not adequately address emotional regulation. Therefore, there is a need for pharmaceutical agents to address neurophysiological problems underlying diseases of dysregulation of food intake.
Cigarette smoking has been recognized as a major public health problem for a long time. However, in spite of the public awareness of health hazard, the smoking habit remains extraordinarily persistent and difficult to break. There are many treatment methods available, and yet people continue to smoke. Administration of nicotine transdermally, or in a chewing gum base is common treatments. However, nicotine has a large number of actions in the body, and thus can have many side effects. It is clear that there is both a need and a demand of long standing for a convenient and relatively easy method for aiding smokers in reducing or eliminating cigarette consumption. A drug that could selectively stimulate only certain of the nicotinic receptors would be useful in smoke cessation programs.
Smoke cessation programs may involve oral dosing of the drug of choice. The drug may be in the form of tablets. However, it is preferred to administer the daily dose over the waking hours, by administration of a series of incremental doses during the day. The preferred method of such administration is a slowly dissolving lozenge, troche, or chewing gum, in which the drug is dispersed. Another drug in treating nicotine addiction is Zyban. This is not a nicotine replacement, as are the gum and patch. Rather, this works on other areas of the brain, and its effectiveness is to help control nicotine craving or thoughts about cigarette use in people trying to quit. Zyban is not very effective and effective drugs are needed to assist smokers in their desire to stop smoking. These drugs may be administered transdermally through the use of skin patches. In certain cases, the drugs may be administered by subcutaneous injection, especially if sustained release formulations are used.
Drug use and dependence is a complex phenomenon, which cannot be encapsulated within a single definition. Different drugs have different effects, and therefore different types of dependence. Drug dependence has two basic causes, that is, tolerance and physical dependence. Tolerance exists when the user must take progressively larger doses to produce the effect originally achieved with smaller doses. Physical dependence exists when the user has developed a state of physiologic adaptation to a drug, and there is a withdrawal (abstinence) syndrome when the drug is no longer taken. A withdrawal syndrome can occur either when the drug is discontinued or when an antagonist displaces the drug from its binding site on cell receptors, thereby counteracting its effect. Drug dependence does not always require physical dependence.
In addition drug dependence often involves psychological dependence, that is, a feeling of pleasure or satisfaction when taking the drug. These feelings lead the user to repeat the drug experience or to avoid the displeasure of being deprived of the drug. Drugs that produce strong physical dependence, such as nicotine, heroin and alcohol are often abused, and the pattern of dependence is difficult to break. Drugs that produce dependence act on the CNS and generally reduce anxiety and tension; produce elation, euphoria, or other pleasurable mood changes; provide the user feelings of increased mental and physical ability; or alter sensory perception in some pleasurable manner. Among the drugs that are commonly abused are ethyl alcohol, opioids, anxiolytics, hypnotics, cannabis (marijuana), cocaine, amphetamines, and hallucinogens. The current treatment for drug-addicted people often involves a combination of behavioral therapies and medications. Medications, such as methadone or LAAM (levo-alpha-acetyl-methadol), are effective in suppressing the withdrawal symptoms and drug craving associated with narcotic addiction, thus reducing illicit drug use and improving the chances of the individual remaining in treatment. The primary medically assisted withdrawal method for narcotic addiction is to switch the patient to a comparable drug that produces milder withdrawal symptoms, and then gradually taper off the substitute medication. The medication used most often is methadone, taken orally once a day. Patients are started on the lowest dose that prevents the more severe signs of withdrawal and then the dose is gradually reduced. Substitutes can be used also for withdrawal from sedatives. Patients can be switched to long-acting sedatives, such as diazepam or phenobarbital, which are then gradually reduced.
Gilles de la Tourette""s Syndrome is an inherited neurological disorder. The disorder is characterized by uncontrollable vocal sounds called tics and involuntary movements. The symptoms generally manifest in an individual before the person is 18 years of age. The movement disorder may begin with simple tics that progress to multiple complex tics, including respiratory and vocal ones. Vocal tics may begin as grunting or barking noises and evolve into compulsive utterances. Coprolalia (involuntary scatologic utterances) occurs in 50% of patients. Severe tics and coprolalia may be physically and socially disabling. Tics tend to be more complex than myoclonus, but less flowing than choreic movements, from which they must be differentiated. The patient may voluntarily suppress them for seconds or minutes.
Currently simple tics are often treated with benzodiazepines. For simple and complex tics, Clonidine may be used. Long-term use of Clonidine does not cause tardive dyskinesia; its limiting adverse effect is hypotension. In more severe cases, antipsychotics, such as Haloperidol may be required, but side effects of dysphoria, parkinsonism, akathisia, and tardive dyskinesia may limit use of such antipsychotics. There is a need for safe and effective methods for treating this syndrome.
Glaucoma is within a group of diseases occurs from an increase in intraocular pressure causing pathological changes in the optical disk and negatively affects the field of vision. Medicaments to treat glaucoma either decrease the amount of fluid entering the eye or increase drainage of fluids from the eye in order to decrease intraocular pressure. However, current drugs have drawbacks such as not working over time or causing side effects so the eye-care professional has to either prescribe other drugs or modify the prescription of the drug being used. There is a need for safe and effective methods for treating problems manifesting into glaucoma.
Ischemic periods in glaucoma cause release of excitotoxic amino acids and stimulate inducible form of nitric oxide synthase (iNOS) leading to neurodegeneration. Alpha 7 nicotinic agonists may stimulate the release of inhibitory amino acids such as GABA which will dampen hyperexcitablity. Alpha 7 nicotinic agonists are also directly neuroprotective on neuronal cell bodies. Thus alpha 7 nicotinic agonists have the potential to be neuroprotective in glaucoma.
Persons afflicted with pain often have what is referred to as the xe2x80x9cterrible triadxe2x80x9d of suffering from the pain, resulting in sleeplessness and sadness, all of which are hard on the afflicted individual and that individual""s family. Pain can manifest itself in various forms, including, but not limited to, headaches of all severity, back pain, neurogenic, and pain from other ailments such as arthritis and cancer from its existence or from therapy to irradicate it. Pain can be either chronic (persistent pain for months or years) or acute (short-lived, immediate pain to inform the person of possible injury and need of treatment). Persons suffering from pain respond differently to individual therapies with varying degrees of success. There is a need for safe and effective methods for treating pain.
Finally, the compounds of the present invention may be used in combination therapy with typical and a typical anti-psychotic drugs. All compounds within the present invention are useful for and may also be used in combination with each other to prepare pharmaceutical compositions. Such combination therapy lowers the effective dose of the anti-psychotic drug and thereby reduces the side effects of the anti-psychotic drugs. Some typical anti-psychotic drugs that may be used in the practice of the invention include Haldol. Some a typical anti-psychotic drugs include Ziprasidone, Olanzapine, Resperidone, and Quetiapine.
Compounds of Formula I can be prepared as shown in Scheme 1. The key step in the preparation of this class of compounds is the coupling of commercially-available 3-aminoquinuclidine with the requisite acid chloride (Lv=Cl), mixed anhydride (e.g., Lv=diphenyl phosphoryl, Bis(2-oxo-3-oxazolidinyl)phosphinyl, or acyloxy of the general formula of Oxe2x80x94C(O)xe2x80x94RLv, where RLv includes phenyl or t-butyl), or carboxylic acid (Lv=OH) in the presence of an activating agent. Suitable activating reagents are well known in the art, for examples see Kiso, Y., Yajima, H. xe2x80x9cPeptidesxe2x80x9d pp. 39-91, San Diego, Calif., Academic Press, (1995), and include, but are not limited to, agents such as carbodiimides, phosphonium and uronium salts (such as HATU). 
Preferably, the acid is coupled with the amino-quinuclidine using HATU in the presence of DIEA using CH2Cl2 as the solvent.
It will be apparent to those skilled in the art that the requisite carboxylic acids can be obtained through synthesis via literature procedures or through the slight modification thereof.
One of ordinary skill in the art will recognize that the methods described for the reaction of the unsubstituted 3-aminoquinuclidine (R2=H) are equally applicable to substituted compounds (R2xe2x89xa0H). Such compounds can be prepared by reduction of the oxime of the corresponding 3-quinuclidinone (see J. Labelled Compds. Radiopharm., 53-60 (1995) and J. Med. Chem. 988-995, (1998)). The oximes can be prepared by treatment of the 3-quinuclidinones with hydroxylamine hydrochloride in the presence of a base. The 3-quinuclidinones, where R2=substituted alkyl, or cycloalkyl can be prepared by known procedures (see Tet. Lett. 1015-1018, (1972), J. Am. Chem. Soc. 1278-1291 (1994), J. Am. Chem. Soc. 4548-4552 (1989), Tetrahedron, 1139-1146 (2000)). The 3-quinuclidinones, where R2=aryl, can be prepared by palladium catalyzed arylation as described in J. Am. Chem. Soc. 1473-1478 (1999) and J. Am. Chem. Soc. 1360-1370 (2000).
There are a variety of methods for constructing thioamides. One can treat the corresponding amide with a reagent such as Lawesson""s reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide). See Lawesson et. al. in Bull. Soc. Chim. Belg., 229 (1978)), or P4S10 (see Chem. Rev., 45 (1961). Alternatively one can react a dithiocarboxylic ester with the corresponding quinuclidine to form the same thioamide.